Explore the vast range of titles available.

Trastuzumab deruxtecan (T-DXd) intracranial activity has been observed in small or retrospective patient cohorts with human epidermal growth factor receptor 2–positive (HER2 + ) advanced/metastatic breast cancer (mBC) and stable or active (untreated/previously treated and progressing) brain metastases (BMs). The phase 3b/4 DESTINY-Breast12 study investigated T-DXd in patients with HER2 + mBC and is, to our knowledge, the largest prospective study of T-DXd in patients with BMs in this setting. Patients (stable/active BMs ( n  = 263) and no BMs ( n  = 241)) treated with one or more prior anti-HER2–based regimens received T-DXd (5.4 mg per kg). Primary endpoints were progression-free survival (PFS; BMs cohort) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (non-BMs cohort). Additional endpoints included central nervous system (CNS) PFS, ORR, time to second progression, CNS ORR (BMs cohort), incidence of new symptomatic CNS metastases (non-BMs cohort), time to progression, duration of response, overall survival and safety (both cohorts). No formal hypothesis testing was conducted for this single-arm, open-label study. In the BMs cohort, 12-month PFS was 61.6% (95% confidence interval (CI): 54.9–67.6), and 12-month CNS PFS was 58.9% (95% CI: 51.9–65.3). In the non-BMs cohort, ORR was 62.7% (95% CI: 56.5–68.8). Grade 3 or higher adverse events occurred in 51% (BMs cohort) and 49% (non-BMs cohort) of patients. Investigator-reported interstitial lung disease/pneumonitis occurred in 16% (grade ≥3: 3%) of patients with BMs and 13% (grade ≥3: 1%) of patients without BMs. These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2 + mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761 . In the non-randomized phase 3b/4 DESTINY-Breast12 study, trastuzumab deruxtecan (T-DXd) treatment of patients with HER2 + advanced breast cancer and active or stable brain metastases showed consistent intracranial activity and systemic efficacy of T-DXd.

KMT2C and KMT2D , encoding histone H3 lysine 4 methyltransferases, are among the most commonly mutated genes in triple-negative breast cancer (TNBC). However, how these mutations may shape epigenomic and transcriptomic landscapes to promote tumorigenesis is largely unknown. Here we describe that deletion of Kmt2c or Kmt2d in non-metastatic murine models of TNBC drives metastasis, especially to the brain. Global chromatin profiling and chromatin immunoprecipitation followed by sequencing revealed altered H3K4me1, H3K27ac and H3K27me3 chromatin marks in knockout cells and demonstrated enhanced binding of the H3K27me3 lysine demethylase KDM6A, which significantly correlated with gene expression. We identified Mmp3 as being commonly upregulated via epigenetic mechanisms in both knockout models. Consistent with these findings, samples from patients with KMT2C- mutant TNBC have higher MMP3 levels. Downregulation or pharmacological inhibition of KDM6A diminished Mmp3 upregulation induced by the loss of histone–lysine N -methyltransferase 2 (KMT2) and prevented brain metastasis similar to direct downregulation of Mmp3 . Taken together, we identified the KDM6A–matrix metalloproteinase 3 axis as a key mediator of KMT2C/D loss-driven metastasis in TNBC. Seehawer et al. show that deletion of Kmt2c or Kmt2d promotes brain metastasis in mouse models of triple-negative breast cancer due to altered KDM6A activity and upregulated MMP3 expression, which may constitute a potential therapeutic target.

Brain metastases (BM) are severe incidents in patients with non–small‐cell lung cancer (NSCLC). The controversial value of prophylactic cranial irradiation (PCI) in NSCLC in terms of survival benefit prompted us to explore the possible risk factors for BM in NSCLC and identify the potential population most likely to benefit from PCI. Risk factors for brain metastases in NSCLC are reviewed in this article. Identifying patients with a higher risk of BM could possibly increase the benefit of PCI while reducing the discomfort and risks caused by unnecessary invasive procedures in the NSCLC patient population. Future studies might focus on finding a solid basis for the prediction of the occurrence of brain metastases and for the therapeutic decision on the use of PCI. Brain metastases are a severe incident in patients with non–small‐cell lung cancer (NSCLC) and it is still common. Controversial value of prophylactic cranial irradiation (PCI) in NSCLC in terms of survival benefit prompted us to explore the possible risk factors for brain metastases (BM) in NSCLC and identify the potential population most likely to benefit from PCI. There are several risk factors of brain metastases in NSCLC. Identifying patients with higher risk of BM could possibly make them receive a greater benefit from PCI, then reduce the discomfort and the unnecessary risks caused by invasive procedures. Future study might take into consideration to find solid basis for therapeutic decisions.

Most deaths from cancer are explained by metastasis, and yet large-scale metastasis research has been impractical owing to the complexity of in vivo models. Here we introduce an in vivo barcoding strategy that is capable of determining the metastatic potential of human cancer cell lines in mouse xenografts at scale. We validated the robustness, scalability and reproducibility of the method and applied it to 500 cell lines 1 , 2 spanning 21 types of solid tumour. We created a first-generation metastasis map (MetMap) that reveals organ-specific patterns of metastasis, enabling these patterns to be associated with clinical and genomic features. We demonstrate the utility of MetMap by investigating the molecular basis of breast cancers capable of metastasizing to the brain—a principal cause of death in patients with this type of cancer. Breast cancers capable of metastasizing to the brain showed evidence of altered lipid metabolism. Perturbation of lipid metabolism in these cells curbed brain metastasis development, suggesting a therapeutic strategy to combat the disease and demonstrating the utility of MetMap as a resource to support metastasis research. A method in which pooled barcoded human cancer cell lines are injected into a mouse xenograft model enables simultaneous mapping of the metastatic potential of multiple cell lines, and shows that breast cancer cells that metastasize to the brain have altered lipid metabolism.

In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumour cells (DTCs) are kept dormant, and what wakes them up, are fundamental problems in tumour biology. To address these questions, we used metastasis assays in mice and showed that dormant DTCs reside on microvasculature of lung, bone marrow and brain. We then engineered organotypic microvascular niches to determine whether endothelial cells directly influence breast cancer cell (BCC) growth. These models demonstrated that endothelial-derived thrombospondin-1 induces sustained BCC quiescence. This suppressive cue was lost in sprouting neovasculature; time-lapse analysis showed that sprouting vessels not only permit, but accelerate BCC outgrowth. We confirmed this surprising result in dormancy models and in zebrafish, and identified active TGF-β1 and periostin as tumour-promoting factors derived from endothelial tip cells. Our work reveals that stable microvasculature constitutes a dormant niche, whereas sprouting neovasculature sparks micrometastatic outgrowth. Bissell, Ghajar and colleagues use organotypic culture systems and in vivo mouse and zebrafish models to reveal the distinct effects of different microvascular niches on tumour cell dormancy. They report that although the stable microvasculature promotes cancer cell quiescence through the production of thrombospondin-1, cancer cells residing near neovascular tips are induced to grow through the action of TGF-β and periostin.

Background The goal of this study was to delineate the patterns of distant metastasis from colon adenocarcinoma (CAC) and evaluate the survival differences by metastatic patterns. Methods Using the Surveillance, Epidemiology, and End Results (SEER) database, we extracted patients diagnosed with stage IV CAC between 2010 and 2016. Kaplan‐Meier survival curves were plotted with log‐rank tests to compare overall survival (OS) of patients with different metastatic patterns. Univariate and multivariate Cox proportional hazards regression models were used to evaluate the effects of different metastatic patterns on survival outcomes in terms of OS and disease‐specific survival (DSS). Results A total of 26 170 patients were analyzed. The 3‐ and 5‐year OS were 20.7% and 10.5%, respectively, for patients with stage IV CAC. The most common distant metastatic site was the liver, followed by the lung, bone, and brain, but the frequency differed greatly by histology subtypes. The site of metastasis was a significant prognostic factor for OS and DSS in patients with stage IV CAC, independent of the number of metastatic sites and other clinical and demographic prognostic factors. Using liver‐only metastasis as reference, lung‐only metastasis was associated with better OS (hazard ratio [HR] = 0.82, 95% confidence interval [CI], 0.71‐0.94) and DSS (HR = 0.75, 95% CI, 0.64‐0.88). Older age, black race, unmarried status, grade III/IV tumors, advanced tumor‐node‐metastasis (TNM) stage, proximal colon, elevated preoperative carcinoembryonic antigen (CEA), no surgery of the primary site, and no chemotherapy were independent predictors of poor OS. Conclusions The site of distant metastasis and number of metastasis site were independent prognostic factors for survival of patients with stage IV CAC. This study highlights the need for diverse treatment strategies for patients with different metastatic patterns. Site of distant metastasis is an independent prognostic factor for survival of patients with metastatic colon cancer. Surgery of the primary tumor and chemotherapy offer significant survival benefits for patients with metastatic disease.

Circulating tumour DNA analysis can be used to track tumour burden and analyse cancer genomes non-invasively but the extent to which it represents metastatic heterogeneity is unknown. Here we follow a patient with metastatic ER-positive and HER2-positive breast cancer receiving two lines of targeted therapy over 3 years. We characterize genomic architecture and infer clonal evolution in eight tumour biopsies and nine plasma samples collected over 1,193 days of clinical follow-up using exome and targeted amplicon sequencing. Mutation levels in the plasma samples reflect the clonal hierarchy inferred from sequencing of tumour biopsies. Serial changes in circulating levels of sub-clonal private mutations correlate with different treatment responses between metastatic sites. This comparison of biopsy and plasma samples in a single patient with metastatic breast cancer shows that circulating tumour DNA can allow real-time sampling of multifocal clonal evolution. Individual tumours are heterogeneous with regards to genetic mutations. In this study, the authors use sequencing to follow multiple tumour and plasma samples over 3 years from a breast cancer patient and show mutations detected in the plasma samples could partially reproduce the clonal nature of the primary tumour.

Metastasis of cancer cells to the brain occurs frequently in patients with certain subtypes of breast cancer. In particular, patients with HER2-positive or triple-negative breast cancer are at high risk for the development of brain metastases. Despite recent advances in the treatment of primary breast tumors, the prognosis of breast cancer patients with brain metastases remains poor. A better understanding of the molecular and cellular mechanisms underlying brain metastasis might be expected to lead to improvements in the overall survival rate for these patients. Recent studies have revealed complex interactions between metastatic cancer cells and their microenvironment in the brain. Such interactions result in the activation of various signaling pathways related to metastasis in both cancer cells and cells of the microenvironment including astrocytes and microglia. In this review, we focus on such interactions and on their role both in the metastatic process and as potential targets for therapeutic intervention.

Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS–STING (cyclic GMP-AMP synthase–stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs. In chromosomally unstable tumour cells, rupture of micronuclei exposes genomic DNA and activates the cGAS–STING cytosolic DNA-sensing pathway, thereby promoting metastasis. Chromosomal instability promotes metastasis The cGAS–STING cytosolic DNA-sensing pathway detects the presence of double-stranded DNA in the cytosol of cells, which triggers an inflammatory response. This pathway can be activated by foreign or cellular DNA. Lewis Cantley and colleagues show that the pathway is activated in human cancer cells with chromosomal instability. Improper segregation of chromosomes during cell division leads to the formation of unstable micronuclei, which burst and release their DNA into the cytosol. The resulting inflammatory response involves activation of NF-κB signalling and promotes metastasis in a STING-dependent manner. These findings link chromosomal instability to metastasis and may offer new avenues to preventing the spread of cancer to distant organs.

ABSTRACT Background Brain metastasis represents the most prevalent form of brain tumors in adults, with a rising incidence resulting from significant advancements in cancer detection and therapeutic interventions. Current treatment protocols advocate for whole brain radiotherapy (WBRT) for patients who are not candidates for either surgical resection or stereotactic irradiation. However, cognitive decline remains a major side effect of this treatment modality. Hippocampal‐sparing WBRT (HA‐WBRT) has been shown to decrease brain toxicity, with the main concern being the probability of developing new brain metastasis in the hippocampal avoidance region. Case We report a case of a 73‐year‐old male presenting with multiple brain metastases and treated with HA‐WBRT, who then developed a new single pontine lesion shortly after that was found to be located in an under‐dosed peri‐hippocampal area. We dosimetrically compared the patient's original IMRT plan to three new plans: a standard VMAT plan, an optimized IMRT plan, and an optimized VMAT plan, where optimization incorporated brainstem coverage as a planning objective, resulting in a notable improvement in brainstem dose distribution. Conclusion HA‐WBRT poses a risk of peri‐hippocampal metastasis due to underdosing of the upper brainstem that is inherent in HA‐WBRT plans. Planning techniques should focus on optimizing coverage of the brainstem in an attempt to decrease this uncommon occurrence.